date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly
蛋白酶激活受体 4 (PAR4) 是抗血小板治疗的重要靶点,可降低中风心脏病发作和血栓并发症的风险。PAR4 拮抗剂通过作用于血小板聚集的晚期扩散阶段,可以防止有害和稳定的血栓生长,同时保留初始血栓形成,并可能为其他抗血小板药物提供更安全的替代品。迄今为止,只有两种 PAR4 拮抗剂BMS-986120和BMS-986141已进入血栓形成的临床试验。因此,非常需要开发具有新化学型的强效和选择性PAR4拮抗剂。在本研究中,我们探讨了 quinazolin-4(3 H)-基于 PAR4 的拮抗剂,从其 IDT 类似物开始。通过反复的结构优化,我们开发了一系列对人血小板具有纳摩尔效力的高选择性 PAR4 拮抗剂。其中,13和30g具有 8-苯并[ d ]噻唑-2-基-取代的 quinazolin-4(3 H )-one 结构,显示出最佳活性(h. PAR4-AP PRP IC 50 = 19.6
Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors
作者:Shuang Liu、Congxiang Zha、Kassoum Nacro、Min Hu、Wenge Cui、Yuh-Lin Yang、Ulhas Bhatt、Aruna Sambandam、Matthew Isherwood、Larry Yet、Michael T. Herr、Sarah Ebeltoft、Carla Hassler、Linda Fleming、Anthony D. Pechulis、Anne Payen-Fornicola、Nicholas Holman、Dennis Milanowski、Ian Cotterill、Vadim Mozhaev、Yuri Khmelnitsky、Peter R. Guzzo、Bruce J. Sargent、Bruce F. Molino、Richard Olson、Dalton King、Snjezana Lelas、Yu-Wen Li、Kim Johnson、Thaddeus Molski、Anitra Orie、Alicia Ng、Roy Haskell、Wendy Clarke、Robert Bertekap、Jonathan O’Connell、Nicholas Lodge、Michael Sinz、Stephen Adams、Robert Zaczek、John E. Macor
DOI:10.1021/ml500053b
日期:2014.7.10
series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the
[EN] DEAZAGUAINE COMPOUNDS AS JAK2 V617F INHIBITORS<br/>[FR] COMPOSÉS DE DÉAZAGUANINE UTILISÉS EN TANT QU'INHIBITEURS DE V617F DE JAK2
申请人:INCYTE CORP
公开号:WO2022140231A1
公开(公告)日:2022-06-30
The present application provides deazaguaine compounds that modulate the activity of the V617F variant of JAK2, which are useful in the treatment of various diseases, including cancer.
Access to C(sp<sup>3</sup>) borylated and silylated cyclic molecules: hydrogenation of corresponding arenes and heteroarenes
作者:Arzoo Chhabra、Sabrina Reich、Timothy M. Shannon、Robert E. Maleczka、Milton R. Smith
DOI:10.1039/d4ra00491d
日期:2024.3.26
Readily available and bench stable catalyst. Tolerates a variety of functional groups including orthogonal functionality. Circumvents the limitations of sp3 C–H borylation.
[EN] IRREVERSIBLE MUTEGFR INHIBITORS<br/>[FR] INHIBITEURS IRRÉVERSIBLES DE MUTEGFR
申请人:[en]BAYER AKTIENGESELLSCHAFT
公开号:WO2023213882A1
公开(公告)日:2023-11-09
Compounds of formula (I) processes for their production and their use as pharmaceuticals.